January 18, 2012

Nationally there are 17,000 people on the waiting list for a liver transplant. Yet according to A. Sidney Barritt, IV, M.D., M.S.C.R., surgeons are able to perform only about 6,000 transplants annually. And, unfortunately, the obesity and diabetes epidemics in this country may be reducing the number of viable organs for transplantation each year. Thus, science which advances the understanding of how best to treat patients and prevent mortality while they wait for transplants is vital.

Barritt and colleagues from UNC-Chapel Hill funded, in part, by an NIH KL2 grant through the North Carolina Translational and Clinical Sciences (NC TraCS) Institute studied one of the factors that may affect mortality of patients awaiting transplant – the density of gastroenterology (GI) specialists in their home communities. He presented his findings at the annual Liver Meeting of the American Association of the Study of Liver Disease and received an AASLD Presidential Poster of Distinction award in November.

Previous studies have looked at patients’ geographic distance from the transplant center, hypothesizing that the greater the distance, the lower the transplant rate. Instead, Barritt and his team considered the density of GI subspecialists in communities and found a correlation: the more GI subspecialists patients have in their home communities, regardless of how far they lived from the transplant center, the better the outcome.

This study showed that among patients referred for liver transplant, the number of gastroenterologists in their home hospital service area independently increases the odds of receiving a liver transplant by 16% for each additional gastroenterologist per 100,000 population. Increasing Model for End-stage Liver Disease (MELD) score and hepatocellular carcinoma also increase the odds of receiving a transplant. Medicaid and Medicare insurance coverage are detrimental to a patient’s odds of receiving a liver transplant, but are better than no insurance coverage at all.

“We were not looking at referral patterns. We were not looking at whether a gastroenterologist was more likely to send you to UNC,” said Barritt. “We were looking at whether the number of gastroenterologists in a community helps keep you alive and a viable transplant candidate from referral to ultimately getting a transplant.”

“Access to local subspecialty care improved the odds of transplant for our patient population most likely because we are a centrally located tertiary care transplant center and many of our patients continue to receive medical care locally. Access to local experts is a great boon to our center in co-managing these patients and we rely heavily on their expertise to get chronically and often critically ill patients through to liver transplant. As our referral base measures more than 500 miles in diameter, we are unable to follow some of our patients on a weekly basis. Additionally, when our medical center has no available beds for inpatient transfers, our colleagues around the state help facilitate patient care locally,” said Barritt.

The project also tested a clinical transplant database at UNC to see whether it is valid for use as a research database. The investigators hope that in the future they can combine these data with that of certain other transplant centers so they can conduct studies with more generalizable findings than research currently available from large single-center studies or from the United Network of Organ Sharing database, which lacks some patient specific data.

Barritt is an assistant professor in the Department of Medicine, Division of Gastroenterology and Hepatology, UNC School of Medicine. He is also a KL2 Scholar, in the second year of three years of support by NC TraCS. The KL2 program objective is to train and develop junior investigators who will become the next generation of successful translational researchers. It does this by providing classroom and experiential training, mentoring, funding for research and, perhaps most importantly, protected research time.

Jan. 18 (Bloomberg) -- Two experimental pills from Bristol- Myers Squibb Co. cleared the hepatitis C virus in 36 percent of patients who failed existing drugs, in a small study that may lead to a new oral-therapy approach against the liver disease.

The study released today is the first to suggest that difficult hepatitis C cases may be cured without using the injected drug interferon, said Anna Lok, the lead study author and director of hepatology at the University of Michigan in Ann Arbor. Interferon, a mainstay of existing treatment, causes unpleasant side effects including fatigue and flu-like symptoms.

Drug companies including Bristol-Myers, Merck & Co., Gilead Sciences Inc., and Vertex Pharmaceuticals Inc. are racing to come up with interferon-free treatment. The new results in 21 patients show that such a therapy will be possible, Lok said.

Oral treatments with fewer side effects would vastly increase the number of patients treated, according to an editorial in the New England Journal of Medicine, where the study was published.

“We are on the threshold of a treatment revolution that will greatly improve the effectiveness of HCV therapy,” wrote Raymond Chung, a gastroenternologist at Massachusetts General Hospital in Boston. He called it “a watershed moment in the annals of HCV therapy.”

The study compared Bristol-Myers’s two pills in combination with interferon to the pills alone in 21 hepatitis C patients who weren’t helped by existing therapy. It found that 4 of 11 patients had undetectable virus 24 weeks after treatment with Bristol’s experimental oral drugs daclatasvir and asunaprevir.

Adding injectable drugs, however, boosted the response rate. Results showed that 9 of 10 patients who got the two oral drugs plus interferon and a fourth drug, ribavirin, for 24 weeks had no detectable virus 24 weeks after stopping therapy.

“The combination of drugs we picked may not be the best, and we need to tweak it and find the best combination,” Lok said in a telephone interview from Ann Arbor.

Hepatitis C can be spread through blood and infected needles. (Centers for Disease Control and Prevention)

By Shari Roan, Los Angeles Times / For the Booster Shots blog

January 18, 2012, 2:12 p.m.

A major advance in treating hepatitis C appears to be on the horizon. Researchers reported Wednesday that combining two antiviral medications was effective in stopping the infection in some patients who were not helped by the traditional treatment.

Progress in fighting hepatitis C infection is of high importance because millions of Americans have the virus. However, the standard treatment with the medication interferon, while effective in many people, is linked to severe side effects. "The challenge ... has been to identify regimens that are more effective, shorter, and have a better side-effect profile," said Dr. Raymond T. Chung, director of hepatology at Massachusetts General Hospital.

Hepatitis C is an infectious disease that can cause liver inflammation and damage. It's spread through exposure to infected blood, such as via contaminated needles or through sexual contact.

The new study, published in the New England Journal of Medicine, is a phase-2 trial of 21 people with hepatitis C who had not responded to previous therapy. They were randomly assigned to receive the two antiviral drugs daclatasvir and asunaprevir or those two antivirals with interferon and ribavirin (another drug used to treat hepatitis C infection).

The study showed that virus activity was halted in 36% of the patients receiving only the two antiviral medications over 24 weeks of treatment. Stopping the virus from replicating halts the infection. All but one of the patients in the second group, who were receiving the combination of four medications, showed a positive response to the medication after 24 weeks.

The research, while preliminary, proves that it may be possible to treat hepatitis C infection with antivirals only. Patients with a type of virus called genotype 1b had a particularly strong response to the antivirals. "Overall, these results suggest that further research with combinations of direct-acting antiviral agents, with or without [interferon] and ribavirin, is warranted," wrote the authors, led by Dr. Anna S. Lok, at the University of Michigan Medical Center.

Chung, who wrote a commentary accompanying the study, said: "We are on the threshold of a treatment revolution that will greatly improve the effectiveness of hepatitis C virus therapy by dramatically increasing the number of persons treated."

Studies are underway to further evaluate the effect of combining antiviral medications for hepatitis C treatment.

Phase II Investigational Data Published Today in the New England Journal of Medicine

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced the full results, published in the New England Journal of Medicine, from a Phase II clinical trial in patients with hepatitis C virus (HCV) genotype 1 who had not responded to prior therapy with PEG-interferon alfa and ribavirin (‘null responders’1). The study demonstrated that its primary endpoint of the achievement of sustained virologic response 12-weeks post-treatment (SVR12) is possible with a direct-acting antiviral (DAA)-only combination containing daclatasvir and asunaprevir (4/11 patients, including two of two patients infected with HCV genotype 1b). This study was the first study to demonstrate the possibility that hepatitis C can be cured (defined as sustained virologic response 48 weeks post-treatment or SVR48) without the use of interferon. The study also demonstrated that 100 percent (10/10) of these difficult-to-treat patients dosed with quadruple therapy containing daclatasvir and asunaprevir in combination with PEG-Interferon alfa and ribavirin achieved SVR12.

In this study there were no serious adverse events on treatment or discontinuations due to adverse events. Diarrhea was the most common adverse event in both groups (73% and 70%).

“Even with the recent approval of two protease inhibitors, treatment of hepatitis C patients who have not responded to PEG-interferon alfa and ribavirin has limited success. Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in null responders,” said lead investigator Anna Lok, MD, FRCP, director of clinical hepatology and professor in the department of internal medicine at the University of Michigan Medical School in Ann Arbor. “The data seen in this study with Bristol-Myers Squibb’s investigational DAAs daclatasvir and asunaprevir, either as DAA-only therapy or as part of quadruple therapy, are encouraging as we work to advance hepatitis C therapy for this difficult-to-treat patient population. This study also shows for the very first time that sustained viral responses can be achieved without the use of interferon and ribavirin.”

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an investigational, oral, selective NS3 protease inhibitor.

Eleven patients were randomized to receive dual DAA therapy for 24 weeks. Seven of the 11 patients (64%) in Group A achieved undetectable viral load by week four, and five patients remained undetectable at the end of treatment. Of these 11 patients, one patient relapsed at four (4) weeks post treatment while four patients (36%) had sustained virological response at 12 weeks post-treatment (SVR12). In follow-up to 48-weeks post treatment, no additional cases of viral relapses were observed.

Six patients, all with HCV genotype 1a, experienced viral breakthrough on dual DAA therapy, and analysis of HCV sequences following breakthrough confirmed resistance to both antivirals. With the addition of PEG-interferon alfa and ribavirin to their regimen (rescue therapy), four of the six patients achieved undetectable viral load. Two of these patients relapsed following the treatment period and two remained undetectable, one with 14 weeks and one with 42 weeks of post treatment follow-up. Two of the six patients did not achieve undetectable HCV RNA and treatment was discontinued.

Ten patients were randomized to receive quadruple therapy for 24-weeks. Six of the 10 patients (60%) in Group B achieved undetectable HCV RNA by week four. Ten of the 10 patients (100%) were undetectable by the end of treatment, and all 10 achieved SVR12. No patients experienced viral relapse during 48 weeks of post-treatment observation.

Safety

In the study, there were no serious adverse events on treatment, no deaths, and no treatment discontinuations due to adverse events. Most adverse events were mild to moderate, and the most common AEs were diarrhea (group A: 8/11, 73%; group B: 7/10, 70%), fatigue (group A: 6/11, 55%; group B: 7/10, 70%), headache (group A: 5/11, 45%; group B: 5/10, 50%), and nausea (group A: 2/11, 18%; group B: 5/10, 50%).

Six patients (four from group A, including two receiving rescue therapy, and two from group B) experienced elevated liver enzymes [ALT >3x upper limit of normal (ULN)] which did not require treatment discontinuation or dose interruptions, and all patients stabilized or improved with continued therapy. Six patients, all of whom received PEG-interferon alfa and ribavirin, experienced Grade 3 or 4 neutropenia, a blood disorder characterized by an abnormally low number of white blood cells.

About the Study

This open-label, phase IIa study evaluated the antiviral activity and safety of the combination of daclatasvir and asunaprevir with and without PEG-Interferon alfa and ribavirin in 21 HCV genotype 1 null responders. Patients in the study were randomized to receive one of two treatment regimens for 24 weeks. The 11 patients in Group A received dual-DAA therapy with daclatasvir 60 mg once daily and asunaprevir 600 mg twice daily, both taken orally. The 10 patients in Group B received quadruple therapy with daclatasvir 60 mg once daily, asunaprevir 600 mg twice daily, PEG-interferon alfa 180 µg once weekly, and ribavirin 1000-1200 mg daily (according to body weight) in two divided doses. The primary study objective was to determine the proportion of patients achieving undetectable viral load (HCV RNA <10 IU/mL) 12 weeks post-treatment (SVR12). This dual-DAA combination is now in Phase III development.

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is advancing a portfolio of compounds that aims to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer. The Company’s hepatitis C pipeline includes a portfolio of compounds with different mechanisms of action, pursuing both biologics as well as small molecule antivirals. These compounds are being studied as part of multiple novel treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies. Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials and is currently in Phase III development. Asunaprevir, also known as BMS-650032, is an NS3 protease inhibitor in Phase III development for hepatitis C.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of pharmaceutical products.Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations.No forward-looking statement can be guaranteed.Among other risks, there can be no guarantee that the compound described in this release will move from exploratory development into full product development, that clinical trials of this compound will support a regulatory filing, or that the compound will receive regulatory approval or become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2010, in our Quarterly Reports on Form 10-Q, and our Current Reports on Form 8-K.Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

NEW YORK (Reuters Health) Jan 13 - Research funded by the National Institutes of Health shows that rituximab is an effective treatment for refractory mixed cryoglobulinemic vasculitis in patients with hepatitis C.

"Unlike conventional forms of immunosuppressive therapy often used to treat this disease, rituximab was well tolerated and did not worsen the underlying viral hepatitis," said lead investigator Dr. Michael C. Sneller in email to Reuters Health.

Pegylated interferon alpha and ribavirin can result in sustained remission, according to the researchers, but more than 50% of patients with HCV genotype 1, the most common in Europe and the Americas, do not respond.

Rituximab, however, can potentially deplete the expanded population of B cells - although there's been some concerns that it may increase HCV replication.

In an open label study, Dr. Sneller - based at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland - and colleagues randomly assigned 24 patients to four weekly infusions of rituximab, or to continue with best available therapy. Everyone in the trial had either failed attempts to control the lymphoproliferative disease with interferon alpha and ribavirin, or they were intolerant of those drugs.

Patients in the rituximab group could continue on their immunosuppressive medications, but they could not increase the dose or receive new immunosuppressants or plasma exchange.

In the control group, patients were maintained on their current regimen and were allowed to increase or initiate new immunosuppressive treatments as needed.

At six months, 10 of the 12 rituximab patients (83.3%) were in remission, compared to only one control subject (8%).

Of the two rituximab patients not in remission at that point, one had to withdraw after two infusions because of febrile reactions. The other was in remission at four months but subsequently relapsed.

There were no adverse effects in terms of viremia or transaminase levels.

The researchers conclude that rituximab can induce sustained remissions, and "was well tolerated and did not appear to increase HCV replication or worsen the underlying hepatitis."

Dr. Sneller added in his email: "Rituximab may be a safer, more effective alternative to standard immunosuppressive therapy for patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy was not effective."

Abstract and Introduction

Abstract

Hepatitis C virus (HCV) infection is a major cause for liver transplantation worldwide. Still, HCV re-infection of the graft occurs in almost all cases. Most liver transplant recipients experience episodes of graft hepatitis associated with fibrosis progression and graft failure. Clinical management of graft hepatitis can be challenging as in addition to rejection and HCV-induced hepatitis various other factors might be involved including toxic liver injury, steatohepatitis, ischaemic bile duct lesions or infections with other pathogens. Treatment options are often contradictory for different causes of graft hepatitis, and the role of distinct immunosuppressive drugs has been discussed controversially. Corticosteroids increase the infectivity of HCV by altering expression levels of entry factors and other immunosuppressive agents may have diverse effects on HCV replication and fibrosis progression. Interferon alpha-therapy of hepatitis C shows limited efficacy and tolerability in liver transplant recipients and may also cause rejection. In this review we summarize the current knowledge on mechanisms of liver injury in post-transplant hepatitis C, discuss the pros and cons of immunosuppressive agents in this specific setting and describe potential novel approaches to prevent HCV reinfection.

Introduction

Around 160 million people are chronically infected with the hepatitis C virus (HCV), representing 2.2% of the world population.[1,2] The geographic distribution of HCV-infected individuals varies largely between 0.1% in Northern Europe and up to 20% in Egypt.[3–6] HCV is a highly variable enveloped RNA virus that infects hepatocytes. Based on sequence analyses, HCV can be grouped into seven different genotypes and more than 100 subtypes within the Flaviviridae family.[7,8]

Patients with acute HCV infection stay asymptomatic in the majority of cases and fail to clear the virus spontaneously.[9,10] Chronic hepatitis C can lead to hepatic inflammation, fibrosis, cirrhosis (10–20%) and hepatocellular carcinoma (HCC; 1–4% per year in cirrhotic patients).[4,9,11] Until 2011 the standard of care for chronic HCV infection has been combination therapy with pegylated interferon alpha (PEGIFN-α) and ribavirin inducing a sustained virological response (SVR), i.e. HCV RNA negativity 6 months after completion of therapy,[12] in 40–50% of patients infected with the most prevalent HCV genotype 1.[13,14] Successful treatment is associated with an improved clinical long-term outcome even though HCC can still develop in cirrhotic patients after HCV has been eliminated.[11,15] Very recently, two inhibitors of the HCV NS3/4A protease, boceprevir and telaprevir have been approved for the treatment of chronic hepatitis C. Triple therapy with a protease inhibitor, PEG-IFNa and ribavirin has substantially improved response rates now approaching 70%-80% for HCV genotype 1 infection.[16]

HCV Recurrence After Liver Transplantation

Chronic infection with HCV is a major cause of end-stage liver disease and a leading indication for orthotopic liver transplantation (OLT) worldwide. However, re-infection of the graft by HCV particles present in the blood stream is almost universal and at least 25% of patients will develop liver cirrhosis after transplantation within 5–10 years.[17,18] Once cirrhosis is established, transplanted patients show an accelerated natural history with decompensation rates of as high as 40% after 12 months.[19] To date, there is no safe and effective way to prevent HCV recurrence. Moreover, patients with recurrent hepatitis can develop a severe cholestatic hepatitis C syndrome characterized by jaundice shortly after transplantation in the absence of biliary obstruction, particular high HCV RNA levels and a very high risk for liver failure.[18] Subsequently, graft loss caused by recurrent HCV infection is the most important reason to consider re-transplantation. Some data suggest that the outcome of hepatitis C after liver transplantation has worsened during the last decades.[20] Across different countries and transplantation programs, the 5-year post-transplantation survival rate for hepatitis C patients is significantly lower as compared to patients who underwent liver transplantation for other chronic liver diseases. Factors being associated with graft loss in HCV-infected patients included an older donor age, steatosis of the donor organ, specific immunosuppressive regimens (discussed later), female sex, a high necroinflammatory activity in the allograft 1 year after transplantation and high HCV viral loads (Table 1).[21–23] In addition, several additional factors have been discussed to influence the long-term outcome of graft hepatitis C such as herpes virus infections,[24] the degree of human leucocyte antigen (HLA) matching[25] or the IL28b genotype of the donor and the recipient.[26,27]

Cellular immune responses by both T cells and NK cells are thought to play a major role in the pathogenesis of chronic hepatitis C after transplantation. HCV-specific T-cell responses have been linked with improved histological and clinical outcomes[28,29] and are also associated with spontaneous HCV clearance after liver transplantation.[30] Genotypes of killer cell immunoglobulin-like receptors and their donor HLA ligands which determine NK cell activities may also play an important role in the recurrence and progression of hepatitis C in liver transplant recipients.[31] An interesting study from Japan showed that adoptive immunotherapy 3 days after liver transplantation with activated lymphocytes extracted from the liver allograft perfusate can result in markedly reduced HCV RNA titres of the recipient confirming the importance of immune cells to control HCV infection after liver transplantation.[32]

In general, HCV RNA levels are higher after OLT than before and high virus titres are associated with a worse long-term outcome of these patients.[33] More specifically, serum HCV RNA levels increase rapidly from the second-week post-transplantation and peak by the fourth postoperative month. HCV RNA levels at 1 year after liver transplantation are 10- to 20-fold higher than pretransplant levels.[34] Viral quasispecies composition differs after liver transplantation as compared to pretransplant sera[35] and may also be involved in the long-term outcome of graft hepatitis.[36] However, detailed mechanisms of how high viral loads and distinct viral compositions contribute to the accelerated disease progression in graft hepatitis C are still poorly defined.

Prevention of HCV Re-infection After Liver Transplantation

Considering the severe clinical course of post-transplant hepatitis C, one of the major unmet needs is the development of strategies to prevent re-infection of the liver graft after transplantation. Pretransplant treatment with PEG-IFNa and ribavirin of patients on the waiting list to prevent HCV reinfection is possible only in few individuals as PEG-IFNa treatment can induce severe infectious complications in decompensated liver disease.[37,38] Moreover, no prophylactic vaccine is yet available to prevent HCV infection.[39] Thus, alternative strategies to prevent HCV reinfection during or very early after transplantation should be explored.

In general, agents preventing viral cell entry should be of particular value (Fig. 1). These include antibodies against one or all essential HCV cellular entry factors, neutralizing antibodies against the HCV envelope proteins E1 and/or E2 envelope or drugs targeting HCV entry by interaction with the virion or a cellular entry factor.

Figure 1. Targets to prevent hepatitis C virus recurrence.

Four cellular factors have been described as essential for HCV entry: the tetraspanin molecule CD81, the scavenger receptor class B member I (SR-BI) and the tight junction proteins claudin-1 and occludin.[40] Interestingly, neutralizing antibodies against CD81 are able to block HCV entry in vitro and also in immunodeficient mice transplanted with human hepatocytes, the best currently available small animal model of HCV infection.[41] Anti-CD81 antibodies are currently in early clinical development but programs using antibodies against the other three entry factors are less advanced.

Neutralizing antibodies against the HCV envelope proteins E1 and E2 could also represent a promising approach to avoid HCV re-infection. However, efforts to elicit neutralizing antibody responses by immunization with E1E2 envelope proteins have had limited success. The main challenge here is the enormous genetic variability of the virus. Present within the chronically infected host is not a single isolate of HCV but rather a population of related yet different viral variants that has been referred to as a 'quasispecies swarm'. The swarm contains a vast repertoire of preformed variants that allow rapid escape from selective pressures such as neutralizing antibodies or anti-viral drugs. It has been shown that during chronic infection, HCV continuously escapes from the host's neutralizing antibody response.[35,42] Nonetheless, efforts to target HCV glycoproteins continue and recently, Garrone et al.[43] reported the development of a vaccine platform to generate HCV-neutralizing antibodies that are based on retrovirus-derived virus-like particles pseudotyped with heterologous E1 and/or E2 proteins. These particles induced neutralizing antibodies in mice and also in macaques and cross-neutralized other HCV genotypes. Overall, the application of broad cross-neutralizing anti-HCV antibodies to prevent HCV reinfection still seems to be reasonable approach. This strategy has been highly successful in hepatitis B virus infection where the combination of passive immunization with anti-HBs antibodies and HBV polymerase inhibitors is able to prevent HBV reinfections in all patients.[44]

Another possibility to inhibit HCV entry is the development of small molecules targeting one of the four cellular entry factors. ITX 5061 is an orally bioavailable compound blocking the HCV receptor scavenger receptor BI protein.[45] ITX-5061 had a good safety profile in animal toxicology studies and also in clinical studies. Currently, the potency of ITX-5061 is evaluated in an open-label, proof-of-concept Phase 1b study in liver-transplanted patients (http://www.clinicaltrials.gov).

Silibinin, a major component of silymarin, is a plant-derived compound that is used for the treatment of HCV infection although its precise mechanism of action is still not known in detail.[46] In 2010, it was shown for the first time that high doses of intravenous silibinin monotherapy prevented graft re-infection after OLT in a patient with chronic hepatitis C[47] which has been confirmed in another case report.[48] However, a much larger controlled study is needed to verify that intravenous silibinin is indeed safe and effective to prevent HCV re-infection after liver transplantation.

Recently, two other already well-known molecules have been shown to inhibit HCV entry: the green tea catechin EGCG and the tyrosine kinase inhibitor erlotinib. Erlotinib blocks HCV entry by inhibition of the activity of the EGF-receptor which is required for formation of CD81-claudin-1 co-receptor associations.[49] EGCG inhibits viral attachment to the target cell as well as cell-to-cell transmission between adjacent cells.[50] Both drugs are already FDA approved for other clinical applications; and EGCG is known to be innocuous in humans, readily available and cheap. Both inhibitors may provide a new approach to prevent HCV infection in the setting of liver transplantation, and future clinical studies are needed to test these in vitro observations in patients.

Besides entry blockers, more advanced direct acting antivirals (DAA) targeting other phases of the replication cycle may also be useful to prevent HCV re-infection. However, almost all DAAs in development have only been tested in compensated chronic HCV infection and their role in the peri-transplant setting remains to be defined. Clearly, this is challenging as the peri-transplant population is more vulnerable. Rapid emergence of drug resistance will prevent monotherapy with certain classes of DAAs including HCV protease inhibitors.[51] However, nucleoside or nucleotide analogous inhibiting the HCV polymerase as well as cyclophilin inhibitors show a very high resistance barrier and thus will likely be part of interferon-free regimens aiming to prevent HCV replication in the transplanted graft.[16,52] Potential drug–drug interactions have to be considered as several DAAs in clinical development for HCV infection are metabolized via the cytochrome P450 3A4 and thus may interfere with immunosuppressive agents.

Thus, several approaches to prevent graft re-infection are currently being pursued. At this stage, no clear favourite has emerged and the goal to prevent HCV reinfection may well remain elusive for several years to come.

Treatment of HCV Re-infection After Transplantation

As long as no potent drugs or neutralizing antibodies are available to prevent HCV recurrence after liver transplantation, re-infection can still be treated with a combination of pegylated interferon alpha and ribavirin. However, the efficacy of this treatment is limited mainly by the poor tolerability in liver transplant recipients, and thus SVR rates are lower than in immunocompetent nontransplanted individuals.[12] Overall, SVR rates after liver transplantation for HCV genotype 1 infection are around 25–30%.[53] Furthermore, prolonged therapy seems to be required even in patients infected with the easier to treat genotypes 2 and 3 and extending antiviral therapy for more than 48 weeks might prevent virological relapse in many patients.[54,55] IL28B genotypes of both the donor and the recipient are associated with response to PEG-IFNa-based treatment after liver transplantation, and determination of the IL28b genotype may therefore be useful in clinical practice to decide which patient should receive antiviral therapy.[27] Importantly, successful treatment reduces liver-related complications in recurrent HCV infection.[56]

Even though interferon alpha can be beneficial for many patients, it has to be considered that antiviral therapy can promote rejection especially in the early phase after transplantation.[57] Thus, liver transplant recipients receiving standard antiviral therapy need to be monitored for acute cellular rejection and chronic ductopenic rejection. In addition, de novo autoimmune hepatitis may develop and immunological phenomena may even occur after treatment has been stopped. As the clinical course of HCV infection is largely influenced by co-factors, it is of particular importance in liver transplant recipients to avoid co-morbidities including ischaemic-type bile duct lesions and liver steatosis.

The use of the novel NS3/4A protease inhibitors seems to be limited in patients after liver transplantation as it has been shown that telaprevir increases tacrolimus blood levels by approximately 70-fold – precluding its use outside of clinical trials.[58] Co-administration with telaprevir also affected cyclosporine exposure and cyclosporine half-life, but to a lesser extent. No data on drug–drug interactions between calcineurin inhibitors (CNI) and boceprevir are currently available. Clinical trials are under way to determine the safety of efficacy of triple therapy of hepatitis C in liver transplant recipients. Whether combinations of PEG-IFNa with other NS3/4A protease inhibitors or with calcineurin inhibitor-free immunosuppressive regimens are feasible remains to be determined.

Currently, more than 100 novel HCV inhibitors are under preclinical and clinical investigation. These can broadly be divided in direct antiviral agents (DAA) and host factor targeting antivirals (HTA).[59] While DAAs target the virus directly and include NS3/4A protease inhibitors (first & second generation), NS5B polymerase inhibitors and NS5A inhibitors, HTAs target essential cellular factors like cyclophilin A, microRNA122 and CD81 antibodies. Disadvantages of some but not all DAA classes are that they are not effective against all HCV genotypes and that viral resistance is anticipated to become a major problem. HTAs may show broad activity across HCV genotypes and pose a higher barrier to drug resistance in comparison with DAA.[16] It is expected that some of the novel drugs will reach the market in 2015; however, none of the new anti-HCV drugs are currently being evaluated in HCV-infected liver transplant recipients. The ultimate goal will be to introduce safe interferon-free combination therapies without significant drug–drug interactions leading to cure from HCV infection within a limited time frame.

Immunosuppression and Graft Hepatitis C

As HCV re-infection cannot be prevented and curative treatment is unsuccessful in the majority of cases, the question arises whether there are ways to optimize post-transplant management, most notably the immunosuppressive regimen used, to minimize the risk of transplant hepatitis and graft loss. Advances in the development of novel immunosuppressive drugs have resulted in an improved clinical outcome after transplantation and transformed liver transplantation into a routine clinical procedure with overall reasonable long-term results. However, individualization of immunosuppressive therapy owing to the underlying disease is still a major goal to enhance graft survival especially in HCV-positive individuals. Furthermore, it has been suggested that the type of immunosuppressive therapy might be responsible for the worse outcome of HCV-positive individuals after liver transplantation observed in recent years.[60]

Calcineurin inhibitors form the backbone of immunosuppression in the majority of liver transplant recipients. The discovery of CNI in the early 1970s and the FDA approval of cyclosporine A (CsA) in 1983 were major milestones for the immunosuppressive management of transplant recipients and increased 1-year graft survival rates from 24% in the late 70s to up to 60% in the 80s.[61] Two CNIs, tacrolimus (Tac) and CsA, are currently approved for immunosuppression after liver transplantation. There is a large experience with both compounds and some differences in efficacy and the side effect profile became evident over the years. Therapy with Tac is associated with a higher incidence of post-transplant diabetes mellitus, while CsA treatment leads more frequently to dyslipidaemia, hypertension, hirsutism and gingival hyperplasia.[62] Tacrolimus treatment may also cause more often hearing impairments, which is a common phenomenon in liver-transplanted patients.[63] Tac is about 100 times more potent than CsA and exerts its action by binding to the FK binding protein 12 (FKBP12), while CsA binds to cyclophilins (e.g. cyclophilin A). Importantly, both of these complexes inhibit calcineurin, a pivotal enzyme in T-cell receptor signalling and activation, which dephosphorylates the transcription factor NF-AT (nuclear factor activating T cell). NF-AT regulates the activity of genes coding for IL-2 and other cytokines in T cells[62] and thus inhibition of calcineurin prevents T-cell activation. Effects on other immune cells have also been noted, e.g. the function of regulatory T cells may be altered by both CsA and Tac.[64]

Cyclophilin A, the target protein of CsA, is not only involved in T-cell activation but also serves HCV as an essential host factor for viral replication.[65] For this reason, CsA very efficiently suppresses HCV RNA replication in vitro. In contrast, treatment with Tac has no effect on HCV RNA levels.[66] This observation has led to the clinical development of non immunosuppressive CsA analogues for the treatment of HCV infection. The cyclophilin A inhibitor alisporivir is currently the most advanced HTA in development, phase II studies have shown good efficacy and very low rates of viral resistance[52,67] and phase III studies for the treatment of chronic hepatitis C patients are ongoing. While alisporivir seems promising in the nontransplant population, the antiviral effect of CsA did not lower HCV viremia in patients after liver transplantation[68] or in a humanized mouse model.[69] Even though, some earlier studies suggested that immunosuppression with cyclosporine might be associated with a better histological outcome of graft hepatitis C.[70] However, the far majority of several subsequent studies did not identify major differences between CsA and Tac in the outcome of HCV infection after liver transplantation as nicely summarized by Berenguer et al. already in 2007.[71] Conversely, a recent retrospective study with more than 8000 HCV-positive liver-transplanted individuals showed that patient death, graft failure, failure owing to recurrent disease and acute cellular rejection were slightly enhanced in the CsA-treated group in comparison with the Tac group.[72] These results may cast doubt on the targeted long-term administration of CsA to HCV-infected liver transplant recipients. However, as part of strategies to avoid HCV re-infection, it might be helpful to employ a CsA-based immunosuppressive regimen in the early phase after transplantation as CsA has a clear additive antiviral effect in vitro.[73] Moreover, some studies suggested that immunosuppression with CsA enhances SVR rates in liver transplant patients treated with interferon alpha and ribavirin.[53,74] Finally, CsA may have advantages concerning drug–drug interactions if novel HCV protease inhibitors are explored as CsA drug levels were less affected than Tac levels when co-administered with telaprevir.[58]

Besides the question of the optimal CNI for HCV-positive liver transplant recipients, the use of steroids after transplantation of HCV patients has been a matter of debate for several years. While it is widely accepted that steroids should be avoided in individuals with HBV infection after liver transplantation, conflicting data have been published for hepatitis C. Clearly, repeated administration of high doses of corticosteroids to treat rejection is associated with more rapid fibrosis progression and poor long-term outcome of graft hepatitis C.[75] Several studies confirmed that there is a strong correlation between steroid bolus therapies of acute rejection episodes and severe recurrence of hepatitis C.[76–78] Moreover, an interim analysis of the American HCV-3 study showed that a steroid-free immunosuppression regime was superior to steroid containing regimes regarding fibrosis progression which is in line with European experience demonstrating that immunosuppression without steroids reduces bacterial infections and improves histological short-term evolution of HCV recurrence.[79] Besides the immunosuppressive effects of glucocorticoids, a recent in vitro study has revealed a direct stimulation of HCV infection by steroids. This was mediated through an upregulation of SR-BI and occludin, two crucial HCV entry factors, suggesting a novel direct mechanism of steroid-dependent exacerbation of HCV infection after liver transplantation.[66] Taken together, it is widely accepted that immunosuppressive regimens after liver transplantation for hepatitis C should avoid steroid boli therapies, if possible. Overall, immunosuppression without steroids is safe after liver transplantation and has been shown to reduce infectious and metabolic complications. However, low-dose corticosteroids may not necessarily have to be avoided in HCV infection after liver transplantation. If steroids are used, slow rather than rapid tapering should be preferred.[80]

The impact of other immunosuppressive agents including mycophenolate mofetil, azathioprine or interleukin-2 inhibitors on HCV recurrence remains controversial. For all of these drugs, conflicting studies have been published indicating both positive and negative effects on the course of HCV re-infection after transplantation. However, large high-quality prospective studies with a long-term follow-up are lacking. Thus, no recommendation can be given at this stage for preferential usage or avoidance of any of these compounds in the context of graft hepatitis C.

Conclusion

Prevention and treatment of HCV re-infection after liver transplantation remains a major unsolved clinical challenge. HCV-positive patients have poorer long-term outcomes after liver transplantation in comparison with patients with other underlying liver diseases. While treatment with pegylated interferon alpha and ribavirin can cure up to one-third of HCV-positive liver-transplanted patients, there are many promising drugs in clinical and preclinical development targeting either the virion or essential host factors. Strategies to prevent HCV re-infection include neutralizing antibodies or drugs targeting cellular HCV entry factors. Unfortunately, it will take at least several years until most of these drugs will reach routine clinical practice. Immunosuppressive medications may alter the course of hepatitis C after transplantation but conclusive data on the use of distinct regimens for HCV-infected transplant recipients are lacking. Thus, almost 30 years after the approval of the first calcineurin inhibitor and 23 years after the discovery of HCV, the optimal immunosuppressive strategy in HCV-positive liver transplant recipients still remains to be defined. However, acute rejection episodes and the need for steroid boli should be avoided as steroid bolus treatment is associated with reduced graft and patient survival and increase HCV infectivity.

Received 23 June 2011; received in revised form 26 July 2011; accepted 2 August 2011. published online 30 August 2011.

Summary

Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.

Introduction

Infection with the hepatitis C virus (HCV) results in various clinical manifestations in addition to inflammatory and fibrotic injury to the liver [1], [2]. Common among these are dermatological conditions and systemic disorders affecting the skin [3]. In some cases, cutaneous signs or symptoms may provide the first and only clue to the existence of an underlying HCV infection [4]. Treatment of dermatological manifestations of HCV through eradication of the virus is therefore important in effective patient management, although this alone is not a major justification for HCV treatment [5]. Existing and in-development antiviral therapies, however, are also associated with dermatological adverse events (AEs). In addition to reviewing the dermatological manifestations of HCV and its treatments, this paper provides practical guidance on the diagnosis and appropriate management of rash events during treatment with the recently approved HCV protease inhibitor telaprevir, in order that their impact on treatment outcomes can be limited.

Cutaneous diseases strongly linked to HCV infection

There are several cutaneous conditions that have a strong association with HCV infection. These are outlined below and summarized in Table 1.

Table 1. Cutaneous diseases strongly linked to HCV infection.

Mixed cryoglobulinemia

Mixed cryoglobulinemia (MC) is a systemic vasculitis that affects mainly the small and, less frequently, medium-sized vessels and is attributable to the expansion of B cells producing pathogenic immunoglobulin M (IgM) with rheumatoid factor (RF) activity. MC leads to clinical manifestations ranging from the so-called MC syndrome (purpura often with skin ulcers, arthralgia, and asthenia) to lesions with neurological and renal involvement due to small-vessel vasculitis [8], [9]. In a prospective study of 1614 HCV-infected patients, 40% experienced MC, and 15% developed MC vasculitis [3] Up to 80–90% of MC vasculitis cases are associated with HCV infection [8], [9] In addition to eradication of HCV infection and symptomatic alleviation, treatment of MC aims to suppress B-cell clonal expansion and cryoglobulin production. The choice of the most appropriate treatment is dependent on the extent of disease activity and organ involvement [8], [10].

Porphyria cutanea tarda

HCV is the most common viral infection associated with porphyria cutanea tarda (PCT), reported in 70–90% of PCT cases in southern Europe and 20% in northern Europe where infection is less prevalent and sunlight exposure is lower [6]. Presentation usually involves vesiculobullous eruption on skin exposed to ultraviolet light such as the back of the hands and the face, caused by deposits of uro- and heptacarboxy-porphyrins in the skin, which promote photon-driven formation of singlet oxygen species [6], [11]. These excess porphyrins are produced chiefly in the liver, and impaired liver function relating to high hepatic iron levels may provide a clue to a causal link between HCV and PCT that is yet to be fully established. Ribavirin-associated haemolysis will increase the iron load in treated patients with chronic hepatitis C and may trigger symptomatic PCT.

Lichen planus

Like PCT, the causal relationship between lichen planus and HCV is unclear [12] Nevertheless, a recent Cochrane meta-analysis found strong correlation between the two conditions. The risk of HCV infection was significantly higher for patients with lichen planus than for those without, while individuals infected with HCV also had an increased risk of having lichen planus [7].

Pruritus and other skin conditions

While pruritus is reported frequently in HCV-infected individuals, [3], [13], [14], [15] it is also a symptom of a range of hepatic co-morbitities that are common in HCV-infected individuals. It is not possible, therefore, to rule out other liver-related causes for pruritus besides the HCV infection itself [6], [16].

Association with HCV infection has been suggested for cutaneous polyarteris nodosa [17], and for a variety of other dermatological conditions including psoriasis, urticaria, and erythema multiforme (EM) [6]. However, most reported associations lacked sufficient evidence to establish a strong causal link with HCV.

Dermatological AEs with pegylated interferon alfa-2a or alfa-2b plus ribavirin are well known, accounting for >10% of all interferon-associated side effects [18]. There is some overlap between the safety profile of interferon-based regimens and other HCV-associated dermatological conditions, meaning distinguishing between infection and treatment in terms of causality may be difficult [16]. Other miscellaneous side effects have been reported, such as hair growth abnormalities and skin pigmentation, and are reviewed elsewhere [16].

Dermatological adverse events with peginterferon/ribavirin combination therapy tend towards a uniform entity of dermatitis, characterized by generalized pruritus and skin xerosis, with eczematiform lesions accentuated by erythematous papules and microvesicles that are often excoriated, predominantly located on the extremities and on truncal skin sites exposed to friction [22]. Management of these eruptions can be achieved with the same approach as for eczema (topical corticosteroids and emollients), usually without the need for discontinuation of the antiviral treatment [16].

Skin reactions with HCV direct-acting antiviral agents

The recent approval by the US FDA of the new HCV direct-acting antivirals (DAAs) Boceprevir [26], and Telaprevir [27] as part of triple combination therapy with the existing peginterferon/ribavirin regimen has begun a new era in HCV treatment. Phase III trials of DAA-based combination therapy in treatment-naïve and previously treated HCV genotype 1-infected patients indicate that significant improvements in sustained virological response rates can be achieved compared with peginterferon/ribavirin alone [28], [29], [30], [31]. Furthermore, DAAs offer the potential to reduce overall treatment duration to less than 48weeks in around half of treatment-naïve patients.

The new treatment era, however, will bring additional patient management considerations for HCV-treating physicians. Dermatological AEs in particular have been reported with a higher frequency in trials of the HCV protease inhibitors telaprevir, [28], [29], [32], [33], [34] boceprevir [30], [31], and BI 201335 [35] as part of triple combination regimens than with peginterferon/ribavirin alone. Furthermore, rash and photosensitivity with BI 201335 appeared to be dose-dependent in Phase IIb trials, with higher rates of moderate and severe rash, and discontinuation due to rash and photosensitivity, reported in patients receiving a higher dose [35]. The mechanism of these side effects is currently unclear, although these preliminary data suggest that the management of dermatological reactions will remain important going forwards.

Data from Phase II/III telaprevir clinical trials

Primary efficacy and safety results from five placebo-controlled Phase II/III trials of telaprevir (PROVE1, PROVE2, PROVE3, ADVANCE, and REALIZE), in which 2012 patients received at least one dose of telaprevir and 764 patients received at least one dose of placebo, have recently been reported in detail [28], [29], [32], [33], [34]. Within this population, 1346 patients received the standard dose of telaprevir: 750mg every 8h, for 12weeks, in combination with peginterferon/ribavirin, followed by peginterferon/ribavirin alone (T12PR). Herein we describe a pooled analysis of the dermatological safety profile of telaprevir in these patients.

Dermatological AEs were recorded using special search categories (SSC) for ‘rash’ and ‘pruritus’. A full characterization of the skin eruptions, and potential underlying mechanisms, will be presented elsewhere, but the majority of events recorded with the ‘rash’ SSC term can be more accurately described as eczematous dermatitis, associated with pruritus, and xerosis. Here, however, we use the SSC terms ‘rash’ and pruritus consistent with the reporting of the clinical trial results.

During the telaprevir/placebo treatment phase, rash, and pruritus were among the AEs occurring more frequently (>5% difference) with telaprevir than placebo. During the telaprevir/placebo dosing phase, 55% and 51% of patients treated with T12PR had rash and pruritus, respectively, compared with 33% and 26% of placebo-treated patients (Fig. 1A).

Fig. 1. Incidence of rash (SSC) in telaprevir Phase II/III placebo-controlled trials in patients receiving telaprevir for 12weeks in combination with peginterferon/ribavirin, followed by peginterferon/ribavirin alone (T12PR). (A) Overall incidence during the telaprevir/placebo treatment phase in the T12PR and PR arms; (B) incidence by Grade during the telaprevir treatment phase in the T12PR arms only; (C) incidence of rash in the T12PR and PR arms during the telaprevir/placebo treatment phase by 4-week periods and during the overall treatment phase by 12-week periods [36], [37].

In the telaprevir trials, rash events were graded by severity into four grades (Table 3). More than 90% of rash (SSC) events with telaprevir were Grade 1 or 2 (mild/moderate). Of the 746 (55%) cases of rash (SSC), 495, 186, and 65 were Grades 1, 2, and 3, respectively, representing 37%, 14%, and 5% of the overall T12PR-treated population (Fig. 1B). Examples of Grades 1 and 2 dermatitis are shown in Fig. 2. In the majority (92%) of cases, progression of rash to a more severe grade did not occur [36]. A small proportion (6% [78/1346]) of all T12PR-treated patients required discontinuation of telaprevir as a result of skin conditions. Following treatment discontinuation, symptoms commonly resolved.

* EM is not life threatening. Careful consideration of discontinuing treatment is needed if the reaction appears different to the general dermatitis/rash, gives rise to suspicion of SJS/TEN or DRESS, or progresses in severity.

The incidence of rash (SSC) during the telaprevir/placebo phase and the overall treatment phase are shown in Fig. 1C [37]. Approximately 50% of rash events started during the first 4weeks, with the remaining 50% starting between weeks 5–12. The median time to onset of rash (any grade) was 25 (range 1–350) days [36]. Therefore, skin eruptions can occur at any time during telaprevir treatment. Following the end of telaprevir dosing at week 12, all patients continued to receive peginterferon/ribavirin, whereupon it is noticeable that the incidence of rash was comparable between telaprevir and placebo-treated patients.

Severe cutaneous adverse reaction

A systematic retrospective assessment by expert dermatologists was made of all 221 Grade 3 rash events, rash events leading to discontinuation of any study drugs, or rash serious AEs occurring in Phase III telaprevir trials [36]. In total, 208 (94%) of these cases were reported in patients receiving telaprevir-based therapy (N=1257) [28], [29]. This assessment revealed 13 patients receiving a telaprevir-based regimen who presented with a suspected severe cutaneous adverse reaction (SCAR). Three cases of Stevens–Johnson Syndrome (SJS, 1 definite, 1 probable, and 1 possible) and 11 cases of drug reaction with eosinophillia with systemic symptoms (DRESS, 1 definite, 2 probable, 8 possible) were reported (in one patient, both diagnoses were suspected) [36]. Among the three SJS cases, one occurred 11weeks after telaprevir discontinuation and was not considered related to telaprevir. Of the two suspected SJS cases that occurred during the telaprevir treatment phase, one was considered by the expert dermatologists as possible SJS, and the other as probable SJS. Among the 11 suspected cases of DRESS, three were confirmed [36]. One of these DRESS cases has been reported separately and is shown in Fig. 2[38]. All cases of reported SJS resolved, 10 cases of reported DRESS resolved, 1 patient was lost to follow-up.

SJS (and its more severe form, toxic epidermal necrolysis [TEN]) and DRESS have a very different presentation but also a different degree of severity. SJS and TEN are very acute events, with a mortality rate of 25% during hospitalization [39], [40]. The rate of mortality for SJS is estimated to be 13%, with a mortality rate of 39% for TEN [41] depending on the SCORTEN severity score [42]. DRESS is more progressive and less severe with a mortality of around 10% [39], [40], [41], [42], [43]. Both reactions require an early diagnosis for proper management, which includes discontinuation of treatment (although the need for urgent diagnosis is more acute with SJS/TEN). Precise documentation and research of risk factors is also needed to adequately quantify and minimize the risk posed.

Rash management plan

The rate of discontinuation of all study drugs as a result of cutaneous AEs was lower in telaprevir Phase III trials than in Phase II trials, [36] following incorporation of a rash management plan into the study protocols (Table 4) [28], [29]. Although a rash management plan was implemented during the ongoing Phase II trials, the majority of patients had already completed the telaprevir dosing period by this time. All patients in Phase III trials, however, were treated following the implementation of the rash management plan at the beginning of the trials.

* Discontinuation based on discontinuation of peginterferon, since per-protocol patients had to discontinue all other drugs if peginterferon was discontinued.

The rash management plan outlined in the Phase III trial protocols provides clear guidance for HCV-treating physicians on how to classify (Table 3) and manage rash events, with the objective of minimizing the impact of cutaneous reactions while enabling continuation of antiviral therapy where possible [28], [29]. Grade 1 or 2 (mild or moderate) rash does not require treatment discontinuation, and can be primarily treated using emollients/moisturizers and topical corticosteroids. Permitted topical or systemic antihistaminic (including diphenhydramine, hydroxyzine, levocetirizine, and desloratadine) drugs may also be used, based on local prescribing guidelines. Regular follow up is important, with advice to the patient to limit exposure to sun/heat and wear loose-fitting clothes. Grade 3 rash requires immediate discontinuation of telaprevir. Symptomatic treatment as above may also be employed. Ribavirin interruption (with or without peginterferon) is required within 7days of stopping telaprevir if the Grade 3 rash does not improve, or sooner if it worsens [28], [29].

However, in case of any reasonable suspicion or diagnosis of SJS, TEN, DRESS (also known as drug-induced hypersensitivity syndrome [DHS] or drug-induced delayed multiorgan hypersensitivity), acute generalized exanthematous pustulosis (AGEP), or a skin rash that is considered life-threatening, patients in Phase III telaprevir trials were required to immediately and permanently discontinue all medication [28], [29].

Perspectives on practical guidance for management of dermatological adverse events with telaprevir

The authors reviewed the available clinical trial data on telaprevir-related dermatological AEs and strategies for their management, with the aim of providing practical guidance for HCV-treating physicians. The key conclusions are presented here. These recommendations seek to allow the physician and patient the best chance of eradicating HCV, enabling them to recognize and respond appropriately to serious dermatological events while optimizing the likelihood for viral clearance with telaprevir-based therapy. Furthermore, to avoid exposing patients to the risk of severe drug-induced cutaneous reaction, HCV-treating physicians should be able to distinguish between usual dermatitis and SCAR.

Good skin care practice

In the case of Grade 1 or 2 dermatitis, patients may benefit from guidance on optimal skin care techniques that could mitigate skin symptoms and allow optimal antiviral therapy to be maintained for as long as possible. Emollient creams and lipid-rich lotions, rather than aqueous lotions or ointments, are effective and well-accepted by patients and should be prescribed as prophylactic baseline skin treatment. The patient should be instructed that proper skin care requires at least 15min and should become a daily habit in order to become effective. This is best performed immediately after a shower or bath, when the skin is still hydrated. Application of the emollient should begin with the hands, feet, and the skin around the large joints, followed by the large skin surfaces of the trunk and extremities, and end with the neck, face, and skin folds. If required, class 3 potent topical corticosteroids can be used. Dosage can be measured by the ‘fingertip’ rule: one fingertip of cream equates to about 0.5g, sufficient to treat an area equivalent to two palms. By assessing the affected skin surface by units of palm surfaces, the therapist can accurately dose the required amount of topical corticosteroid required for a given treatment interval. Fig. 3 illustrates the basic principles of topical steroid dosing. Topical calcineurin inhibitors such as tacrolimus are not currently indicated, as they may yield high serum levels when skin barrier function is impaired.

Fig. 3. Guidance on the efficient administration of a topical steroid: the fingertip rule. (A) One fingertip of cream equates to around a 0.5g steroid dose, (B) sufficient to treat an area equivalent to two palms. By assessing the affected skin surface by units of palm surfaces, the amount of topical treatment required for a given treatment interval can be accurately assessed.

Recognition and classification of skin eruptions with telaprevir

Dermatological manifestations with telaprevir-based therapy can be considered to constitute two conditions. The large majority of cutaneous reactions represent a single dermatitis entity. This telaprevir-related dermatitis generally begins during the first 4weeks of therapy, but can occur at any time during treatment. This eczematous dermatitis reaction is similar to reactions observed with peginterferon/ribavirin, but occurs with increased frequency and severity. Typical features of such HCV treatment-associated rash also include pruritus and skin dryness, and it is stable or slow to progress. Continuation of telaprevir together with peginterferon/ribavirin treatment is possible in Grade 1 or 2 (mild or moderate) cases, or Grade 3 cases with appropriate management (see below). In contrast, a small remainder of cases can be classified as SCAR, which is typically rare but potentially life-threatening if unrecognized or unmanaged, mandating immediate treatment discontinuation.

Management of grades 1–3 telaprevir-associated dermatitis

In line with the rash management plan implemented in Phase III trials, the telaprevir prescribing information stipulates that Grade 1 and 2 dermatological reactions to telaprevir do not require treatment interruption, but that Grade 3 reactions require telaprevir discontinuation followed by ribavirin and/or peginterferon discontinuation within 7days if the reaction does not improve, or sooner if it worsens [27].

In some cases, Grade 3 dermatitis reactions affecting more than 50% of body surface area but with no signs of SJS, TEN, DRESS, EM or AGEP may be manageable using topical corticosteroids without treatment discontinuation. In such cases, however, hospitalization of the patient is required, and experienced dermatologists should be responsible for patient management and close follow up for signs of progression. It is important for physicians to be aware of the prescribing information for telaprevir and local guidelines for management of dermatological adverse drug reactions.

Appropriate guidelines, as evidenced from the Phase III studies of telaprevir (Table 3), permit the continuation of peginterferon/ribavirin treatment after the cessation of telaprevir in order to optimize the chance of SVR while minimizing the risk of DRESS or SJS. The less common but potentially life-threatening reactions such as SJS, TEN, and DRESS require cessation of all treatment.

AGEP is generally characterized by an acute, widespread edematous erythema with the presence of small non-follicular pustulosis mostly in the folds and the face, and is associated with elevated neutrophils and high fever [40], [44]. The reaction lasts for a few days. While EM is not a life-threatening reaction, there has been some historical confusion between EM and the separate entity of SJS [39], [45]. Ensuring the correct diagnosis is made and appropriate action is taken is therefore important when considering discontinuing antiviral treatment. While SJS is drug-induced, EM usually occurs post-infection and is characterized by typical target lesions, chiefly on the extremities, rather than the widespread macules or blisters associated with SJS [39]. Target lesions are defined as less than 3cm in diameter, with at least 3 ‘zones’: a central zone of dusky erythema or purpura (sometimes blistering), a middle paler area of oedema, and a well-defined outer ring of erythema [46]. All other target lesions lacking this pattern of three zones should be considered atypical target lesions. In cases of suspicion of EM, we would advise that telaprevir discontinuation should be considered, and implemented if the reaction appears different to the general dermatitis reaction, gives rise to any reasonable suspicion of SJS/TEN or DRESS, or progresses in severity.

The severity of telaprevir-associated dermatitis events dictates the frequency of evaluation by the HCV-treating physician. In the case of a Grade 1 event, it is recommended that the patient should be re-evaluated between days 2 and 4 after the onset of rash. Patients with a Grade 2 event should be seen at day 2. Grade 3 events require follow up on days 1, 3, and 7. Additional regular follow-up of patients is required until the reaction is completely resolved.

Guidance for distinguishing between telaprevir-related dermatitis and SCAR

In accordance with the Phase III rash management plan, and in contrast to the telaprevir-related dermatitis, SJS, TEN, DRESS, EM, and AGEP reactions require immediate discontinuation of all treatment (telaprevir, peginterferon, and ribavirin) and referral to a dermatologist. A number of clinical and biological signs and symptoms have been identified from the clinical trial database that may help HCV-treating physicians to distinguish between telaprevir-related dermatitis, where antiviral treatment can often be continued and supportive treatment given, and the less common but potentially more harmful SJS and DRESS reactions. These are illustrated in the algorithm in Fig. 4 and outlined below. (Click to enlarge)

Patients with a rash that appears to be unlike the telaprevir-associated dermatitis should be assessed for signs that may indicate possible DRESS. Criteria that should alert the physician include onset from 5 to 10weeks after first dose, rapidly progressing skin rash, prolonged fever (>38.5°C), and facial edema. If any of these signs are present, the patient should be urgently examined for the following ‘confirmation criteria’: enlarged lymph nodes, eosinophilia, atypical lymphocytes, and rise in alanine transaminase, alkaline phosphatase or creatinine. If any confirmation criteria are found, telaprevir, peginterferon, and ribavirin treatment should be discontinued immediately and permanently, and the patient referred to a dermatologist. It is important to note that there is a greater urgency for prompt diagnosis and appropriate action for SJS and TEN. Patients presenting with mucosal involvement of at least two sites, or with blisters or epidermal detachment (at sites beyond the site of peginterferon injection) should immediately and permanently discontinue telaprevir, peginterferon, and ribavirin and be referred to a dermatologist. Rapidly progressing skin rash, skin pain, and atypical or typical target lesions may also be present in cases of SJS or TEN and should alert the physician to assess the patient for mucosal involvement, blisters or positive Nikolsky signs (epidermal detachment under lateral pressure on erythema).

Summary and conclusions

HCV and its treatment with peginterferon/ribavirin are associated with significant dermatological complications. In the era of DAA-based triple combination therapy, however, management of dermatological AEs will become an even more important consideration for HCV-treating physicians. Effective management strategies will be of great importance in limiting the severity and impact of dermatological side effects on treatment outcomes.

The majority of cutaneous AEs occurring with telaprevir can be classified as a less harmful eczematous dermatitis, associated with pruritus and xerosis. Most cases of this dermatitis reaction are mild or moderate, in which case good skin care practice, coupled with vigilance for the rare signs of more serious reactions, should enable antiviral therapy (peginterferon/ribavirin with or without telaprevir) to be maintained in order to increase the chances of patients achieving an SVR. Rare cases of severe cutaneous reactions including DRESS and SJS have been reported and resolved upon antiviral treatment discontinuation. Even though these cases are rare, special attention to skin symptoms occurring during HCV treatment and strict adherence to the rash management plan is required in order to detect severe cutaneous reactions as early as possible.

Conflict of interest

Patrice Cacoub has been a consultant and invited speaker for Schering Plough, Roche Pharma, Janssen Pharmaceuticals, Servier, Vifor Pharma, Sanofi-Aventis, Pfizer, and has received educational grants from Schering Plough, Gilead, Servier, Vifor Pharma, Glaxo SmithKline; Marc Bourlière has been a consultant and invited speaker for Janssen Pharmaceuticals, Roche Pharma, Schering Plough, Merck, Gilead, BMS, Novartis, and GlaxoSmithKline; Jann Lübbe has received speaker honoraria from Janssen Pharmaceuticals and Roche Pharma; Nicolas Dupin has been a consultant for Janssen Phamaceuticals and Boehringer Ingelheim; Peter Buggisch has been a consultant and invited speaker for Janssen Pharmaceuticals, Roche Pharma, Schering Plough, Merck, Gilead and Novartis; Geoffrey Dusheiko has received consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Human Genome Sciences, Novartis, Pharmasset, Pfizer, Roche–Genentech, Schering-Plough (Merck), Tibotec, Vertex Pharmaceuticals, and ZymoGenetics, travel support from Gilead Sciences, and grant support from Gilead Sciences, Novartis, Pharmasset, Hoffmann–La Roche, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals; Christophe Hézode has been a consultant and invited speaker for Janssen Pharmaceuticals; Odile Picard has been an invited speaker for Janssen Pharmaceuticals; Ramon Pujol has been a consultant for Janssen Pharmaceuticals; Siegfried Segaert has been a consultant and invited speaker for Janssen Pharmaceuticals; Bing Thio has been a consultant and invited speaker for Janssen Pharmaceuticals and has received an educational grant from Janssen Pharmaceuticals; Jean-Claude Roujeau has been a consultant and invited speaker for Boehringer Ingelheim, Janssen Pharmaceuticals, Johnson & Johnson, Medimmune, OM Pharma, Pfizer, Servier, Vertex and has received research grants from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Sanofi-Aventis, Servier and Wyeth.

This clinical review reflects the detailed discussion and opinions of the authors on data and literature reviewed at an advisory board meeting on the dermatological manifestations of HCV treatments held in Paris, France in March 2011. The advisory board meeting was sponsored by Janssen Pharmaceuticals, however the content of this paper does not necessarily reflect the opinions of the meeting sponsor. Medical writing support was provided by Tom Westgate of Gardiner-Caldwell Communications (funded by Janssen Pharmaceuticals), who developed the first draft of the manuscript based on the authors’ recommendations of relevant published papers and the debate and discussion during the meeting. All authors substantially contributed to development of all drafts of the manuscript and have read and approved the final draft. The corresponding author had full access to the source literature and takes full responsibility for the content of the paper and for the decision to submit.

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